This invention relates to the use of dsRNA in synergistic combination with other materials that inhibit viral activity or expression to control or in the treatment of viral diseases.
Double-stranded RNAs (dsRNAs), such as poly I.poly C, can act as biological response modifiers eliciting antiviral, antineoplastic and immunomodulatory activities. Among the pleiotropic effects responsible for these biological responses are induction of interferon (IFN) and other cytokines as well as activation of certain INF-induced enzymes including 2,5-oligoadenylate synthetase and a ribosome-associated protein kinase. These properties make dsRNAs attractive candidates for the treatment of infection by human immunodeficiency virus (HIV), the retrovirus responsible for acquired immunodeficiency syndrome (AIDS). In fact, mismatched dsRNA of the form r(I)..sub.n.r(C.sub.12-14 -U).sub.n (Ampligen) has a low toxicity profile in humans, is active against HIV infection both in vitro and in vivo, and is currently in large-scale, controlled clinical trials of AIDS-related complex (ARC).
The American Foundation for AIDS Research (AmFAR) currently lists over 60 drugs being tested for use in treating ARC and AIDS. This enormous potential of single-agent therapy is compounded by possible synergism in combination therapy. Alternatively, combined therapy has the potential for antagonism as demonstrated in vitro with azidothymidine (AZT) and ribavirin. For these reasons, I decided to characterize the full potential of mismatched dsRNA in the treatment of ARC and AIDS. I accomplished this by performing in vitro multiple drug analyses using mismatched dsRNA as a core drug in combination with other agents that together encompassed at least five different modes of attack on this virus. These agents included rIFN-alpha A, rIFN-beta Ser 17 and rIFN-.sub.y as cytokines; azidothymidine and phosphonoformate (foscarnet) as inhibitors of reverse trasncription; ribavarin as a putative disrupter of mechanisms governing proper mRNA capping; amphotericin B as a lipid-binding molecule with anti-HIV activity; and castanospermine as an inhibitor of glycoprotein processing (1). One of the drugs, azidothymidine, appeared to act synergistically in vitro with mismatched dsRNA as described in earlier application Ser. No. 028,823 filed Mar. 23, 1987, now abandoned.
In this application, I demonstrate that each drug separately had dose-dependent anti-HIV activity which was synergistic with mismatched dsRNA at the most effective doses.